Many patients in the later stages of Parkinson's disease experience periods of acute immobility ("off' periods) that substantially decrease their quality of life. The most effective pharmacological treatments for these acute "off' periods are dopamine agonist drugs, which can rapidly abort "off' periods if delivered quickly into the blood stream via injection. The utility of this form of treatment is, however, limited due to its invasiveness and the inability of many late-stage Parkinson's disease patients to self-administer injections. The aim of this project is to develop an inhalation device that delivers dopamine agonists rapidly into the blood stream in a convenient, non-invasive fashion. We have developed a novel drug delivery technology that involves heating drugs such that they vaporize, but do not degrade, and subsequently cool and condense into small particle aerosols suitable for systemic delivery by inhalation. In Phase I of this proposal, we have constructed a handheld device capable of generating pure aerosols of several dopamine agonists, demonstrated the biological activity of these aerosols in vitro, and confirmed that the aerosol's particle size is appropriate for systemic delivery via deep lung inhalation. In Phase II of this grant we will prove that inhaled dopamine agonists rapidly reverse Parkinson's disease symptoms in an animal model and will conduct all pre-clinical work required to initiate clinical development of inhaled dopamine agonist for treatment of late stage Parkinson's disease. Successful completion of these aims will allow us to move into Phase I clinical testing, which will be funded by a combination of outside investors, FDA funds for the development of orphan drugs, and/or a partnership with a major pharmaceutical company. Eventual FDA approval of inhaled dopamine agonist product for treatment of motor fluctuations in late stage Parkinson's will substantially improve the treatment of this serious and common neurodegenerative disease. [unreadable] [unreadable]